- Email: [email protected]
Thrombolysis
disease free at 30 months. With a mean follow-up of8 months, overall and disease-free survival at one year are 72% and 29%, respectively.
CONCLUSION: The combination ofchemoembolization and RF ablation provides durable local control of liver tumors up to 6 cm. In the absence of a transplant, progression at other sites remains a therapeutic challenge 4:21 PM
Abstract No. 215
Chemoembolization of Metastatic Colorectal Carcinoma after Hepatic Arterial Infusion Pump Chemotherapy. A. Kwak, University a/Pennsylvania Medical Center, Philadelphia, PA, USA· CM Tuite· MC Soulen
PURPOSE: To evaluate response and survival after CAM! EthiodoVPVA chemoembolization in patients with metastatic adenocarcinoma ofthe colon and prior hepatic arterial infusion pump chemotherapy. MATERIALS AND METHODS: Patients eligible for treatment had a pathologic diagnosis of colorectal cancer, bidimensionably measurable liver metastases, as well as adequate renal, cardiac and hepatic function. All patients had failed prior hepatic arterial infusion therapy (HAlT). Chemoembolization with cisplatinum, doxorubicin, mitomycin-C, iodized oil and polyvinyl alcohol particles was perforriled at monthly intervals for 1-3 sessions. Morphologic and biologic response were assessed by comparing the preand 30 day post-treatment cross- sectional imaging and CEA levels using the WHO criteria. RESULTS: Eleven patients were treated with a total of 22 chemoembolization sessions. No patients were untreatable because of infusion pump-related hepatic arterial occlusion. The cumulative survival from the time ofdiagnosis with liver metastases was 90% at one year, 70% at two years and j 7% at three years. Morphologic response could be evaluated in 8 patients. Three patients had stable disease, while 5 patients demonstrated morphologic progression. Biologic response was evaluated in 5 patients. Three patients had a partial response, and one patient each had a minor response or progression. Typical symptoms of postembolization syndrome occurred in all patients. Two patients developed grade 4 biliary toxicity. One patient developed grade 3 hematologic toxicity. There were no major complications after any of the procedures. CONCLUSION: [n this single institution experience, chemoembolization of metastatic colorectal carcinoma after failed hepatic arterial infusion pump chemotherapy provides survival rates double those reported for current systemic chemotherapy regimens and comparable to those reported for HAlT. The incidence of significant toxicity is not increased over that reported for HAlT alone. 4:32PM
Abstract No. 216
Quality of Life Assessment in Patients Undergoing Chemoembolization: A Longitudinal Follow-Up Study. P. Drescher, Medical College o/Wisconsin, Milwaukee, WI, USA· ME Robertson· Ws. Rilling· MR. Crain· K Saeian • J Franco
PURPOSE: To assess the overall health status in patients undergoing hepatic chemoembolization (HCE) utilizing a multiscale health questionnaire (SF-36), and to provide longitudinal follow-up over multiple HCE sessions.
874
MATERIALS AND METHODS: Prospectively, 25 patients with hepatic dominant malignancy undergomg HCE completed the SF-36 questionnaire. All patients had at least 2 HCE, 15
patients (60%) 3 HCE, 6 patients (24%) 4 HCE,and 3 patients (12%) 5 HCE. The average time interval between HCEs was 71 days (range 46 -121 days). The health scales were calculated and averaged for each treatment using the SF-36 standard questionnaire. Comparison was made to an age-matched healthy control and over the course of repeated HCE session.
RESULTS: The compliance to complete the SF-36 was 100%. Compared to an age matched healthy control, the HCE patients scored lower in physical functioning (PF), social functioning (SF), mental health (MH), and signiflcant lower (>50%) in role physical (RP) and role emotional (RE). At the time of the second HCE, patients scored lower in all health scales except for MH compared to the first HCE. Significantly lower scores were found in bodily pain (BP). Over the course ofsubsequent HCE, the scores increased «50%) for vitality and MH and significantly (>50%) increased for RP, RE. Only the score for BP steadily declined over the course of treatment. Over the duration of the study the mortality rate from the underlying disease was 32%. CONCLUSION: Compared to healthy controls, patients undergoing chemoembolization scored lower in 5 out of 8 health scales. HCE appears to be a well-tolerated preserving or even improving many health scales after an initial decline. The increase in scores of physical, emotional and mental components might represent a selection bias for patients with an overaJl prolonged survival.
Scientific Session 28 Thrombectomy/Thrombolysis Thursday, April 11, 2002 3:00 PM - 4:30 PM Moderator(s): Scott Sa vader, MD 3:00PM
Abstract No. 217
Comparison of Alteplase, Reteplase, and Tenecteplase and Effects on Hemostatic Parameters in a Rabbit Model. c.p Semba, BioTherapeutic Unit, Genentech, Inc., San Francisco, CA, USA· A.S. Cheng· KP. McKeever· K Refino • D. Combs· CA. ONeill, et al.
PURPOSE: The unavailability of urokinase in the US has led clinicians to explore alternative thrombolytic agents for catheter-directed thrombolysis in treating acute limb ischemia and deep vein thrombosis. Despite widespread use of thrombolytics,.there exists no pre-clinical comparative safety data evaluating the effects of these agents on changes in coagulation parameters when administered using catheterdirected techniques and empiric dosing schedules. The purpose of this study was to evaluate the effect of alteplase (tPA), reteplase (rPA) and tenecteplase (TNK) on hemostatic parameters using doses and techniques similar to clinical practice in a rabbit model. MATERIALS AND METHODS: The primary endpoints were changes in coagulation parameters at varying drug doses including PT, aPTf, fibrinogen, plasminogen, a-2~antiplasmin, and plasma drug concentrations. Dosing was based upon a 70-kg human and compared to saline controls. Following induction and intubation, femoral cutdowns were performed in male NZW rabbits (2-3 kg). Intravascular catheters were placed in the femoral artery and vein. Subjects did not receive heparin. TPA, rPA, and TNK were infused intravenously into the femoral vein at doses corresponding to 0, 0.5, I, 2, and 10 (mg/h, tPA, TNK; UIb, rPA) for 4 hIs. Artelial blood samples were collected at T = 0, 0.5, 1,2, 3, 4 hrs.
,
RESULTS: A dose-dependent alteration in PT and fibrinogen was observed for all agents. However, tPA and TNT< exhibited significantly lower depletion of systemic fibrinogen and less alteration in baseline PT compared to rPA. TPA maintained a-2-antiplasmin levels to a greater extent than TNK (20% baseline a-2-antiplasmin with 10 mg/h dose only) and rPA (0%,40%, and 50% baseline a-2-antiplasmin with 10,2, and I U/hrdoses, respectively). Plasminogen levels showed similar dose-response changes. CONCLUSION: Pre-clinical evidence in a rabbit infusion model shows significantly less alteration of hemostatic parameters with TPA and TNK compared to rPA and may be related to the different fibrin-affinity, fibrin-specificity properties of the various molecules. The degree of systemic fibrinolysis and abnormal shift in coagulation parameters were highest for rPA. Based on empiric dosing regimens used in current clinical practice, pre-clinical studies suggest that the potential for adverse bleeding events may be reduced with the higher fibrin selective agents and appropriate dosing regimens; further comparative human clinical trials are warranted.
3:)] PM
Abstract No. 218
Tenecteplase (TNK): Protein Stability and Bioactivity of Thawed or Diluted Solutions Used in Peripheral Thrombolysis. c.p Semba, BioTherapeufic Unif. GenenLech,lnc., San Francisco, CA, USA· S. Week· M.K. Razavi • L. Tuomi· T. PaLapojJ
PURPOSE: TNK is a third-generation genetically engineered variant of alteplase with enhanced safety potential used for peripheral thrombolysis, however, dilution/dosing protocols have been established solely upon empiric data. The purpose is to provide quantitative and supportive evidence of the biochemical stability and activity ofTNK solutions used in clinical practice. MATERIALS AND METHODS: Lyophilized TNK was freshly reconstituted in Sterile Water for Injection (5 mg/mL) and used as control. Color/clarity, pH, UV spectrophotometry, HIAC/ROYCO particle counts, and in-vitro clot lysis assays were performed on test samples. Freeze/thaw studies: 2 - 8 mL freshly reconstituted TNK aliquots in glass vials were frozen (- 20°C) and assayed after 4 weeks of storage ± additional freeze/thaw cycle. Freshly rec·onstituted TNK in 10 mL glass aliquots were assayed after 6 freeze/thaw cycles. Dilution studies: Fresh TNK was diluted in 500 mL commercially available NS bags to 0.01,0.02, and 0.05 mg/ mL. Samples were assayed T = 0, 8, and 24 hours at ambient temperature. RESULTS: TNK aliquots met all certified product specifications after 4 weeks frozen storage and after up to 6 freeze/thaw cycles. Dilution samples in NS were stable at 0, 8, and 24 hours with specific activity of 83- 100%. Solutions were clear and colorless at all concentrations and time points tested. CONCLUSION: Tenecteplase (TNK) is biochemically stable following reconstitution and freezing. TNK solutions used in clinical practice (0.01 - 0.05 mg/mL) show preservation of activity up to 24 hours at ambient temperature without visible precipitates. Use of intravenous in-line microfilters is not necessary.
3:22PM
Abstract No. 219
Pulse-Spray Thrombolysis: An In Vitro Study of Dose Distribution with a Dual Catheter Infusion System. s.J. Savader, Mefhodist Hospital. Indianapolis. IN, USA· BJ McAfee· K.A. Suder· D.C. Lanfrip • K.D. Brown
PURPOSE: For large geographic regions of vascular thrombosis, such as that which can occur within the inferior vena cava, iliofemoral veins, or a femore-popliteal bypass graft, it may be desireable to perform thrombolysis simu ltaneously through two catheters to improve the efficiency of the therapy. This in vitro study was designed to determine the relative distribution of fluid volumes (drug dose) that are delivered when two, "Y-connected", pulsespray catheters of the same (paired) and different (unpaired) length, and the same (paired)and different (unpaired) number of side-holes, are infused via a single pulse-spray machine. MATERiALS AND METHODS: A mechanical pulse-spray delivery device was connected via a Y-connector to two pulsespray catheters. Combinations ofcatheters with the same and different length and the same and different number of sideholes, were tested. Catheters 90 ems long with side-hole lengths of5, 10,20,30,40, and 50 cms; and catheters 135 cms long with side-hole lengths of I0, 20, and 50 cms were utilized. All possible combinations of these nine catheters were tested using a set delivery volume of 300 ml normal saline during each offour test runs. Two runs were performed with a checkflow valve (to prevent free-flow of fluid between pulses) and two runs were performed without the valve in place. The fluid was delivered into laboratory grade, 1000 ml graduated cylinders, filled with a gelatin medium to simulate thrombus. Fluid volumes were measured and recorded. The Student-t test was used to compare fluid volumes between the two cylinders (p value < or equal to .05 considered significant). Mean volumes, standard deviation (S.D.), and delivery error (difference between the fluid volume set to be delivered and the measured volume delivered) were also determined. The pulse-spray machine was calibrated twice during the experiment to insure accuracy. RESULTS: With and without the check-flow valve in place, paired catheters (same length and number of side-holes) delivered near equal volumes of fluid (mean with valve, 157 ml vs. 153 ml, P value=.55; mean without valve, 156 ml vs. 158 ml, p value=.40). The delivery error was 2-5% with, and 13-14% withoutthe check-flow valve in place. Both with and without the check-flow valve in place, unpaired catheters (two catheters ofdifferent length and/or side-hole distribution) delivered significantly different fluid volumes (with valve, p=.016; without valve, p=.0004), but a detailed analysis of the fluid volumes delivered with respect to catheter characteristics yielded no detectable pattern. The delivery error was 3-9% with, and 7-16% without the check-flow valve in place. When each ofthe nine catheters were evaluated individually for the volume delivered during all runs, again, no detectable pattern based on length and number of side-holes could be determined. The range of fluid volumes delivered through anyone catheter varied by as much as five-fold. The standard deviation for the volumes delivered ranged from 2257 ml, with 5-31 % ofthe delivered volumes falling outside of +/- I S.D. of the mean. CONCLUSION: This in vitro experiment demonstates that a commercially available pulse-spray machine can be set up to deliver a thrombolytic agent simultaneously through two catheters. Paired catheters reliably and near equally deliver the pump-set volume, but use of the check-flow valve is required to reduce the dosing error to 5% or less. The use of unpaired catheters yields an inconsistant and unpredictable distribution of fluid between the two catheters. The delivery
875
error is about twice that seen with paired catheters, but is still less than 10%. This small, but not insignificant error in dosing, should be taken into consideration when planning patient therapy with a dual catheter delivery system.
3:33PM
Abstract No. 220
Thrombolysis by Application of Ultrasonic Energy to a Titanium Wire: Estimation of Particle Size. 1.F. Polak, Omnisonics Medical Technologies, Boston, MA, USA· F. Chen· R. Marciante· S Bloch· R. Rabiner· B. Hare PURPOSE: To determine the size of particles created during the application of ultrasonic energy to a wire designed to achieve thrombolysis. MATERlALS AND METHODS: Samples ofbovine blood were subjected to ultrasonic energy delivered by a prototype titanium wire (13 cm length; 20 KHz). Three power levels were used above the cavitation threshold of the device. Exposure times were 15 and 30 seconds and sets of5 samples were used. After exposure to ultrasonic energy, samples were washed and the suspension was subjected to sizing in a Laser diffraction particle size analyzer. RESULTS: Median particle size for this series of in-vitro experiments varied between 4.1 and 4.3 microns. Mean values varied between 4.06 and 5.68 microns. Of 30 samples, 20 generated particles of 10 micron or less. In all cases, particles were 50 microDs or less. Particle size did not depend on irradiation time or power delivered. CONCLUSION: Particulates generated during dissolution of thrombus by application of ultrasonic energy along a wire tend to be small and unlikely to cause significant distal embolization. Time (sec)
15 15 15 30 30 30
3:44PM
RESULTS: Rbeolytic device: for alteplase solutions of 0.05 and I mg/mL, the protein recovery was 80-82% and 94-1 00% of targeted concentration, respectively, and the collected protein was fully active, All solutions were clear and colorless after propulsion through the device. Maceration device: for alteplase solutions of 0.05 and I mg/mL, protein recovery was 14-18% and 93-99% of targeted concentration, respectively, and the collected protein was fully active. All solutions appeared opalescent to slightly cloudy after passage through the device. No fragmentation or change in aggregation of protein was observed with either device with undiluted alteplase. However, in dilute solutions, the low protein concentration exceeded the limit of detection by the assay. CONCLUSION: Alteplase solutions may be an alternative to heparinized saline for the rheolytic thrombectomy device, however, significant protein loss and turbidity was observed with the high-speed maceration device. Recovered alteplase fTom both devices remain fully active. Clinical investigation is warranted using thrombolysis-facilitated mechanical thrombectomy as a novel method of pharmacomechanical thrombolysis.
3:55PM
Abstract No. 222
Histological Comparison of a Novel Stationary Basket to a Rotating Basket Thrombectomy Device in an Ovine Artery. c.P. Semba, Stanford University, Stanford, CA, USA· D. DeMarais· SA. Leejlang· C. EversuU· T.1. Fogarty
Power level A B C
% particles <10 >t 82.5
4.3
lOa
4.1
89.3
4.2
A
97.7
4.1
B
100
4.3
PURPOSE: We describe a novel mechanical thrombectomy device (Bacchus™Solem®) which utilizes a stationary basket design and an inner screw-drive to facilitate clot removal exvivo. The purpose ofthis study was to histologically evaluate the changes to the arterial wall comparing the stationary basket (SBD) device to a rotating basket device (RBD; Arrow-PTD
C
100
4.1
®).
Median potticle silO(>t)
Abstract No. 221
Alteplase Stability and Bioactivity after ThrombolysisFacilitated Rheolytic or High-Speed Maceration Thrombectomy. c.P. Semba, BioTherapeutic Unit, Genentech, Inc., San Francisco, CA, USA· S Weck· M.K. Razavi· T. PatapojJ PURPOSE: Emerging alternatives to standard mechanical thrombectomy include use of infusing thrombolytic solutions instead of heparinized saline through the thrombectomy catheter to promote pharmacomechanical lysis. However, these devices exhibit high shear forces that may fragment and denature lytic proteins. The purpose was to determine the viability of alteplase solutions following propulsion through rheolytic or high-speed maceration thrombectomy devices.
S76
native size exclusion chromatography, and in-vitro clot lysis techniques to determine percent protein recovery, percent monomer remaining, and bioactivity of collected protein solution.
MATERIALS AND METHODS: Alteplase was freshly reconstituted (I mg/mL) in steri Ie water or reconstituted then diluted in 250 mL bags ofNS to a targeted concentration of 0.05 mg/mL. The 0.05 and I mg/mL solutions were used as controls. Two types of thrombectomy devices were used: rheolytic (AngioJet Expeedior) and high-speed maceration (Helix Clotbuster). Alteplase solutions (0.05 mg/mL, D= 4; and I mg/mL, n = 4) were delivered through the operating device instead of heparinized saline and collected in glass containers at ambient temperature and assayed by color/clarity,
MATERIALS AND METHODS: The primary endpoint was the grade ofhistological change in the ovine arterial wall (carotid and iliac) architecture following the SBD (N=5) or RBD (N=5) compared to control. The SBD is a motorized handheld thrombectomy device which incorporates an outer stationary wire basket to remove adherent mural clot. The inner axis contains a bi-directional screw-drive which macerates the clot and removes debris fragments ex-vivo under negative pressure. Access was via cutdown and sidebranches ligated for 20 cm. Thru an 8 Fr sheath under fluoro control, each device was passed (unidirectional) 4x while running over 5 cm vessel length. Total device run time was recorded. Vessels were flushed with NS followed by 10% formalin prior to explant and fixation for '::?72 h. The specimens were sectioned and reviewed/scored by a blinded third party histologist. RESULTS: Carotid: significant endothelial changes occurred for both devices C.t. control, however there was less disruption of the intimalJEL and media with the SBD. Iliac: endothelial changes occurred for both devices however, the SBD exhibited less vessel wall trauma to the intima/IEL, media, fewer microthrombi, no loosening of the media, and no neutrophil infiltration of the intima compared to the RBD. There was one technical failure: in one case, the vessel wall prolapsed and became entangled in the wire basket of the RBD. CONCLUSION: The histological changes following mechanical thrombectomy using a novel device 'that incorporates a
stationary outer basket and an inner screw-drive, compared to a standard rotating basket design, are described. Pre-clinical histological analysis demonstrates significantly less vascular wall damage with the SBD compared to the RED. Further human clinical investigation will be required to assess the safety and efficacy of the SB thrombectomy device in native vessels. 4:06PM
Abstract No. 223
Percutaneous Mechanical Thmmbectomy Versus Open Surgery in the Treatment of Acute Limb Threatening Ischemia. K. Kasiralan, University ofNew Mexico School ofMedicine, Albuquerque, NM, USA· K. Ouriel PURPOSE: The aim of the study was to evaluate percutaneous mechanical thrombectomy (PMT) in comparison to open surgical revascularization (OSR) for the treatment of acute limb ischemia. MATERIALS AND METHODS: Patients with acute limb threatening ischemia «14 days) were identified from a prospectively maintained computer registry. The endovascular group had 65 consecutive patients treated with the Angiojet catheter (Possis Medical, Minneapolis, MN) as a stand-alone (n=21) or with adjunctive phannacological thrombolysis (n=44). This group was compared to 79 consecutive patients having undergone open surgical revascularization. The major clinical end points evaluated include death, major amputation, major morbidity, primary patency and 12-month amputation free survival. RESULTS: There was a greater incidence of hypertension (P
4:17PM
Abstract No. 224
FEATURED ABSTRACT
Commentator: Charles E. Ra) •.Jr.
Restoring Flow to Occluded Central Venous Catheters with Use of Alteplase: Safety and Efficacy in 1064 Patients. c.p Semba. BioTherapeutic Unit, Genentech, Inc., San Francisco, CA, USA· S.R. Deitcher • X Ii· L. Resnansky • PA. Hill· E.R. McCluskey
PURPOSE: Thrombosis of central venous access devices (CVADs) is a relatively frequent complication. Alteplase (tPA) has been used to salvage dysfunctional devices. The purpose of this study was to analyze the safety and efficacy following administration ofup to two 2 mg doses ofalteplase in restoring function to thrombosed CVADs. MATERIALS AND METHODS: A combined analysis was perfonned on two pivotal prospective Phase III clinical trials involving 79 centers from November 1999 through December 2000. Patients ~ 2 yrs ofage (and> 10 kg) with dysfunctional non-dialysis CVADs were eligible including PlCCs, apheresis catheters and ports. Alteplase (2 mg/2 mL) was instilled in the lumen of the cvAn and allowed to dwell. For patients with body weight 10 to < 30 kg, 110% of the internal lumen volume ofalteplase (2 mg/2rnL) was administer~d. Ifthe device was still occluded after up to 120 ro, a second alteplase dose was given and allowed to dwell for up to 120 m. Primary efficacy endpoint was restored function after up to 2 doses. Primary safety endpoint was ICH within 5 days. RESULTS: A total of 1070 patients (M 467: F 603; mean age 50.7 yrs, range, 2 - 91:) were eligible and 1064 (99.4%) were treated. Six (0.6%) pts had spontaneous function w/o treatment. Following alteplase, function was restored in 798 (75.0%) after one dose and 905 (85.4%) after up to 2 doses. Efficacy rates were similar among all catheter types (single, double, triple lumen catheters, ports). Serious adverse events reported within 30-days of treatment: ICH (0.0%), embolic events (0.0%), GI bleeding (0.3%), thrombosis (0.3%), and sepsis (0.4%). There were no gender-related differences observed in the rates of adverse events and were similar across age subgroups. CONCLUSION: AJteplase (2 mg/ 2mL) is safe and effective in restoring flow to occluded central venous access devices.
Scientific Session 29 Access Site Management/Closure Devices Thursday, April 11 ,2002 3:00 PM - 4:30 PM Moderator(s): Kenneth D. Murphy, MD
3:00PM
Abstract No. 225
A Novel Access Method for Endovascular Procedures in the Swine Model. Y. Dong, The Cleveland Clinic Foundation, Solon, OH, USA • M Sands· P Rasmussen· J. Perl II PURPOSE: The saphenous artery arises from distal femoral artery and I ies just under the skin at the internal-middle of the thigh. This study evaluates the use of the saphenous artery as an al ternative access for endovascular procedures in the swine model. MATERIALS AND METHODS: Fourteen adult pigs (25-35kg) were used in this study, three pigs from an acute study and eleven from chronic studies. A 1-2 em incision was made and a saphenous artery cutdown was perfonned in 24 sides. Micropuncture sets (Boston Scientific) or 18 G puncture needles were used to access the artery. Different sizes of introducers (4-7 F) were used to establish endovascular access. Angiographic catheters were then used to confLTITI ifthe access was usable. Four saphenous arteries were explanted in the pigs from a chronic study one month after the surgical procedure.
877
CONCLUSION: The combination ofchemoembolization and RF ablation provides durable local control of liver tumors up to 6 cm. In the absence of a transplant, progression at other sites remains a therapeutic challenge 4:21 PM
Abstract No. 215
Chemoembolization of Metastatic Colorectal Carcinoma after Hepatic Arterial Infusion Pump Chemotherapy. A. Kwak, University a/Pennsylvania Medical Center, Philadelphia, PA, USA· CM Tuite· MC Soulen
PURPOSE: To evaluate response and survival after CAM! EthiodoVPVA chemoembolization in patients with metastatic adenocarcinoma ofthe colon and prior hepatic arterial infusion pump chemotherapy. MATERIALS AND METHODS: Patients eligible for treatment had a pathologic diagnosis of colorectal cancer, bidimensionably measurable liver metastases, as well as adequate renal, cardiac and hepatic function. All patients had failed prior hepatic arterial infusion therapy (HAlT). Chemoembolization with cisplatinum, doxorubicin, mitomycin-C, iodized oil and polyvinyl alcohol particles was perforriled at monthly intervals for 1-3 sessions. Morphologic and biologic response were assessed by comparing the preand 30 day post-treatment cross- sectional imaging and CEA levels using the WHO criteria. RESULTS: Eleven patients were treated with a total of 22 chemoembolization sessions. No patients were untreatable because of infusion pump-related hepatic arterial occlusion. The cumulative survival from the time ofdiagnosis with liver metastases was 90% at one year, 70% at two years and j 7% at three years. Morphologic response could be evaluated in 8 patients. Three patients had stable disease, while 5 patients demonstrated morphologic progression. Biologic response was evaluated in 5 patients. Three patients had a partial response, and one patient each had a minor response or progression. Typical symptoms of postembolization syndrome occurred in all patients. Two patients developed grade 4 biliary toxicity. One patient developed grade 3 hematologic toxicity. There were no major complications after any of the procedures. CONCLUSION: [n this single institution experience, chemoembolization of metastatic colorectal carcinoma after failed hepatic arterial infusion pump chemotherapy provides survival rates double those reported for current systemic chemotherapy regimens and comparable to those reported for HAlT. The incidence of significant toxicity is not increased over that reported for HAlT alone. 4:32PM
Abstract No. 216
Quality of Life Assessment in Patients Undergoing Chemoembolization: A Longitudinal Follow-Up Study. P. Drescher, Medical College o/Wisconsin, Milwaukee, WI, USA· ME Robertson· Ws. Rilling· MR. Crain· K Saeian • J Franco
PURPOSE: To assess the overall health status in patients undergoing hepatic chemoembolization (HCE) utilizing a multiscale health questionnaire (SF-36), and to provide longitudinal follow-up over multiple HCE sessions.
874
MATERIALS AND METHODS: Prospectively, 25 patients with hepatic dominant malignancy undergomg HCE completed the SF-36 questionnaire. All patients had at least 2 HCE, 15
patients (60%) 3 HCE, 6 patients (24%) 4 HCE,and 3 patients (12%) 5 HCE. The average time interval between HCEs was 71 days (range 46 -121 days). The health scales were calculated and averaged for each treatment using the SF-36 standard questionnaire. Comparison was made to an age-matched healthy control and over the course of repeated HCE session.
RESULTS: The compliance to complete the SF-36 was 100%. Compared to an age matched healthy control, the HCE patients scored lower in physical functioning (PF), social functioning (SF), mental health (MH), and signiflcant lower (>50%) in role physical (RP) and role emotional (RE). At the time of the second HCE, patients scored lower in all health scales except for MH compared to the first HCE. Significantly lower scores were found in bodily pain (BP). Over the course ofsubsequent HCE, the scores increased «50%) for vitality and MH and significantly (>50%) increased for RP, RE. Only the score for BP steadily declined over the course of treatment. Over the duration of the study the mortality rate from the underlying disease was 32%. CONCLUSION: Compared to healthy controls, patients undergoing chemoembolization scored lower in 5 out of 8 health scales. HCE appears to be a well-tolerated preserving or even improving many health scales after an initial decline. The increase in scores of physical, emotional and mental components might represent a selection bias for patients with an overaJl prolonged survival.
Scientific Session 28 Thrombectomy/Thrombolysis Thursday, April 11, 2002 3:00 PM - 4:30 PM Moderator(s): Scott Sa vader, MD 3:00PM
Abstract No. 217
Comparison of Alteplase, Reteplase, and Tenecteplase and Effects on Hemostatic Parameters in a Rabbit Model. c.p Semba, BioTherapeutic Unit, Genentech, Inc., San Francisco, CA, USA· A.S. Cheng· KP. McKeever· K Refino • D. Combs· CA. ONeill, et al.
PURPOSE: The unavailability of urokinase in the US has led clinicians to explore alternative thrombolytic agents for catheter-directed thrombolysis in treating acute limb ischemia and deep vein thrombosis. Despite widespread use of thrombolytics,.there exists no pre-clinical comparative safety data evaluating the effects of these agents on changes in coagulation parameters when administered using catheterdirected techniques and empiric dosing schedules. The purpose of this study was to evaluate the effect of alteplase (tPA), reteplase (rPA) and tenecteplase (TNK) on hemostatic parameters using doses and techniques similar to clinical practice in a rabbit model. MATERIALS AND METHODS: The primary endpoints were changes in coagulation parameters at varying drug doses including PT, aPTf, fibrinogen, plasminogen, a-2~antiplasmin, and plasma drug concentrations. Dosing was based upon a 70-kg human and compared to saline controls. Following induction and intubation, femoral cutdowns were performed in male NZW rabbits (2-3 kg). Intravascular catheters were placed in the femoral artery and vein. Subjects did not receive heparin. TPA, rPA, and TNK were infused intravenously into the femoral vein at doses corresponding to 0, 0.5, I, 2, and 10 (mg/h, tPA, TNK; UIb, rPA) for 4 hIs. Artelial blood samples were collected at T = 0, 0.5, 1,2, 3, 4 hrs.
,
RESULTS: A dose-dependent alteration in PT and fibrinogen was observed for all agents. However, tPA and TNT< exhibited significantly lower depletion of systemic fibrinogen and less alteration in baseline PT compared to rPA. TPA maintained a-2-antiplasmin levels to a greater extent than TNK (20% baseline a-2-antiplasmin with 10 mg/h dose only) and rPA (0%,40%, and 50% baseline a-2-antiplasmin with 10,2, and I U/hrdoses, respectively). Plasminogen levels showed similar dose-response changes. CONCLUSION: Pre-clinical evidence in a rabbit infusion model shows significantly less alteration of hemostatic parameters with TPA and TNK compared to rPA and may be related to the different fibrin-affinity, fibrin-specificity properties of the various molecules. The degree of systemic fibrinolysis and abnormal shift in coagulation parameters were highest for rPA. Based on empiric dosing regimens used in current clinical practice, pre-clinical studies suggest that the potential for adverse bleeding events may be reduced with the higher fibrin selective agents and appropriate dosing regimens; further comparative human clinical trials are warranted.
3:)] PM
Abstract No. 218
Tenecteplase (TNK): Protein Stability and Bioactivity of Thawed or Diluted Solutions Used in Peripheral Thrombolysis. c.p Semba, BioTherapeufic Unif. GenenLech,lnc., San Francisco, CA, USA· S. Week· M.K. Razavi • L. Tuomi· T. PaLapojJ
PURPOSE: TNK is a third-generation genetically engineered variant of alteplase with enhanced safety potential used for peripheral thrombolysis, however, dilution/dosing protocols have been established solely upon empiric data. The purpose is to provide quantitative and supportive evidence of the biochemical stability and activity ofTNK solutions used in clinical practice. MATERIALS AND METHODS: Lyophilized TNK was freshly reconstituted in Sterile Water for Injection (5 mg/mL) and used as control. Color/clarity, pH, UV spectrophotometry, HIAC/ROYCO particle counts, and in-vitro clot lysis assays were performed on test samples. Freeze/thaw studies: 2 - 8 mL freshly reconstituted TNK aliquots in glass vials were frozen (- 20°C) and assayed after 4 weeks of storage ± additional freeze/thaw cycle. Freshly rec·onstituted TNK in 10 mL glass aliquots were assayed after 6 freeze/thaw cycles. Dilution studies: Fresh TNK was diluted in 500 mL commercially available NS bags to 0.01,0.02, and 0.05 mg/ mL. Samples were assayed T = 0, 8, and 24 hours at ambient temperature. RESULTS: TNK aliquots met all certified product specifications after 4 weeks frozen storage and after up to 6 freeze/thaw cycles. Dilution samples in NS were stable at 0, 8, and 24 hours with specific activity of 83- 100%. Solutions were clear and colorless at all concentrations and time points tested. CONCLUSION: Tenecteplase (TNK) is biochemically stable following reconstitution and freezing. TNK solutions used in clinical practice (0.01 - 0.05 mg/mL) show preservation of activity up to 24 hours at ambient temperature without visible precipitates. Use of intravenous in-line microfilters is not necessary.
3:22PM
Abstract No. 219
Pulse-Spray Thrombolysis: An In Vitro Study of Dose Distribution with a Dual Catheter Infusion System. s.J. Savader, Mefhodist Hospital. Indianapolis. IN, USA· BJ McAfee· K.A. Suder· D.C. Lanfrip • K.D. Brown
PURPOSE: For large geographic regions of vascular thrombosis, such as that which can occur within the inferior vena cava, iliofemoral veins, or a femore-popliteal bypass graft, it may be desireable to perform thrombolysis simu ltaneously through two catheters to improve the efficiency of the therapy. This in vitro study was designed to determine the relative distribution of fluid volumes (drug dose) that are delivered when two, "Y-connected", pulsespray catheters of the same (paired) and different (unpaired) length, and the same (paired)and different (unpaired) number of side-holes, are infused via a single pulse-spray machine. MATERiALS AND METHODS: A mechanical pulse-spray delivery device was connected via a Y-connector to two pulsespray catheters. Combinations ofcatheters with the same and different length and the same and different number of sideholes, were tested. Catheters 90 ems long with side-hole lengths of5, 10,20,30,40, and 50 cms; and catheters 135 cms long with side-hole lengths of I0, 20, and 50 cms were utilized. All possible combinations of these nine catheters were tested using a set delivery volume of 300 ml normal saline during each offour test runs. Two runs were performed with a checkflow valve (to prevent free-flow of fluid between pulses) and two runs were performed without the valve in place. The fluid was delivered into laboratory grade, 1000 ml graduated cylinders, filled with a gelatin medium to simulate thrombus. Fluid volumes were measured and recorded. The Student-t test was used to compare fluid volumes between the two cylinders (p value < or equal to .05 considered significant). Mean volumes, standard deviation (S.D.), and delivery error (difference between the fluid volume set to be delivered and the measured volume delivered) were also determined. The pulse-spray machine was calibrated twice during the experiment to insure accuracy. RESULTS: With and without the check-flow valve in place, paired catheters (same length and number of side-holes) delivered near equal volumes of fluid (mean with valve, 157 ml vs. 153 ml, P value=.55; mean without valve, 156 ml vs. 158 ml, p value=.40). The delivery error was 2-5% with, and 13-14% withoutthe check-flow valve in place. Both with and without the check-flow valve in place, unpaired catheters (two catheters ofdifferent length and/or side-hole distribution) delivered significantly different fluid volumes (with valve, p=.016; without valve, p=.0004), but a detailed analysis of the fluid volumes delivered with respect to catheter characteristics yielded no detectable pattern. The delivery error was 3-9% with, and 7-16% without the check-flow valve in place. When each ofthe nine catheters were evaluated individually for the volume delivered during all runs, again, no detectable pattern based on length and number of side-holes could be determined. The range of fluid volumes delivered through anyone catheter varied by as much as five-fold. The standard deviation for the volumes delivered ranged from 2257 ml, with 5-31 % ofthe delivered volumes falling outside of +/- I S.D. of the mean. CONCLUSION: This in vitro experiment demonstates that a commercially available pulse-spray machine can be set up to deliver a thrombolytic agent simultaneously through two catheters. Paired catheters reliably and near equally deliver the pump-set volume, but use of the check-flow valve is required to reduce the dosing error to 5% or less. The use of unpaired catheters yields an inconsistant and unpredictable distribution of fluid between the two catheters. The delivery
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error is about twice that seen with paired catheters, but is still less than 10%. This small, but not insignificant error in dosing, should be taken into consideration when planning patient therapy with a dual catheter delivery system.
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Abstract No. 220
Thrombolysis by Application of Ultrasonic Energy to a Titanium Wire: Estimation of Particle Size. 1.F. Polak, Omnisonics Medical Technologies, Boston, MA, USA· F. Chen· R. Marciante· S Bloch· R. Rabiner· B. Hare PURPOSE: To determine the size of particles created during the application of ultrasonic energy to a wire designed to achieve thrombolysis. MATERlALS AND METHODS: Samples ofbovine blood were subjected to ultrasonic energy delivered by a prototype titanium wire (13 cm length; 20 KHz). Three power levels were used above the cavitation threshold of the device. Exposure times were 15 and 30 seconds and sets of5 samples were used. After exposure to ultrasonic energy, samples were washed and the suspension was subjected to sizing in a Laser diffraction particle size analyzer. RESULTS: Median particle size for this series of in-vitro experiments varied between 4.1 and 4.3 microns. Mean values varied between 4.06 and 5.68 microns. Of 30 samples, 20 generated particles of 10 micron or less. In all cases, particles were 50 microDs or less. Particle size did not depend on irradiation time or power delivered. CONCLUSION: Particulates generated during dissolution of thrombus by application of ultrasonic energy along a wire tend to be small and unlikely to cause significant distal embolization. Time (sec)
15 15 15 30 30 30
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RESULTS: Rbeolytic device: for alteplase solutions of 0.05 and I mg/mL, the protein recovery was 80-82% and 94-1 00% of targeted concentration, respectively, and the collected protein was fully active, All solutions were clear and colorless after propulsion through the device. Maceration device: for alteplase solutions of 0.05 and I mg/mL, protein recovery was 14-18% and 93-99% of targeted concentration, respectively, and the collected protein was fully active. All solutions appeared opalescent to slightly cloudy after passage through the device. No fragmentation or change in aggregation of protein was observed with either device with undiluted alteplase. However, in dilute solutions, the low protein concentration exceeded the limit of detection by the assay. CONCLUSION: Alteplase solutions may be an alternative to heparinized saline for the rheolytic thrombectomy device, however, significant protein loss and turbidity was observed with the high-speed maceration device. Recovered alteplase fTom both devices remain fully active. Clinical investigation is warranted using thrombolysis-facilitated mechanical thrombectomy as a novel method of pharmacomechanical thrombolysis.
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Abstract No. 222
Histological Comparison of a Novel Stationary Basket to a Rotating Basket Thrombectomy Device in an Ovine Artery. c.P. Semba, Stanford University, Stanford, CA, USA· D. DeMarais· SA. Leejlang· C. EversuU· T.1. Fogarty
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PURPOSE: We describe a novel mechanical thrombectomy device (Bacchus™Solem®) which utilizes a stationary basket design and an inner screw-drive to facilitate clot removal exvivo. The purpose ofthis study was to histologically evaluate the changes to the arterial wall comparing the stationary basket (SBD) device to a rotating basket device (RBD; Arrow-PTD
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100
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Abstract No. 221
Alteplase Stability and Bioactivity after ThrombolysisFacilitated Rheolytic or High-Speed Maceration Thrombectomy. c.P. Semba, BioTherapeutic Unit, Genentech, Inc., San Francisco, CA, USA· S Weck· M.K. Razavi· T. PatapojJ PURPOSE: Emerging alternatives to standard mechanical thrombectomy include use of infusing thrombolytic solutions instead of heparinized saline through the thrombectomy catheter to promote pharmacomechanical lysis. However, these devices exhibit high shear forces that may fragment and denature lytic proteins. The purpose was to determine the viability of alteplase solutions following propulsion through rheolytic or high-speed maceration thrombectomy devices.
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native size exclusion chromatography, and in-vitro clot lysis techniques to determine percent protein recovery, percent monomer remaining, and bioactivity of collected protein solution.
MATERIALS AND METHODS: Alteplase was freshly reconstituted (I mg/mL) in steri Ie water or reconstituted then diluted in 250 mL bags ofNS to a targeted concentration of 0.05 mg/mL. The 0.05 and I mg/mL solutions were used as controls. Two types of thrombectomy devices were used: rheolytic (AngioJet Expeedior) and high-speed maceration (Helix Clotbuster). Alteplase solutions (0.05 mg/mL, D= 4; and I mg/mL, n = 4) were delivered through the operating device instead of heparinized saline and collected in glass containers at ambient temperature and assayed by color/clarity,
MATERIALS AND METHODS: The primary endpoint was the grade ofhistological change in the ovine arterial wall (carotid and iliac) architecture following the SBD (N=5) or RBD (N=5) compared to control. The SBD is a motorized handheld thrombectomy device which incorporates an outer stationary wire basket to remove adherent mural clot. The inner axis contains a bi-directional screw-drive which macerates the clot and removes debris fragments ex-vivo under negative pressure. Access was via cutdown and sidebranches ligated for 20 cm. Thru an 8 Fr sheath under fluoro control, each device was passed (unidirectional) 4x while running over 5 cm vessel length. Total device run time was recorded. Vessels were flushed with NS followed by 10% formalin prior to explant and fixation for '::?72 h. The specimens were sectioned and reviewed/scored by a blinded third party histologist. RESULTS: Carotid: significant endothelial changes occurred for both devices C.t. control, however there was less disruption of the intimalJEL and media with the SBD. Iliac: endothelial changes occurred for both devices however, the SBD exhibited less vessel wall trauma to the intima/IEL, media, fewer microthrombi, no loosening of the media, and no neutrophil infiltration of the intima compared to the RBD. There was one technical failure: in one case, the vessel wall prolapsed and became entangled in the wire basket of the RBD. CONCLUSION: The histological changes following mechanical thrombectomy using a novel device 'that incorporates a
stationary outer basket and an inner screw-drive, compared to a standard rotating basket design, are described. Pre-clinical histological analysis demonstrates significantly less vascular wall damage with the SBD compared to the RED. Further human clinical investigation will be required to assess the safety and efficacy of the SB thrombectomy device in native vessels. 4:06PM
Abstract No. 223
Percutaneous Mechanical Thmmbectomy Versus Open Surgery in the Treatment of Acute Limb Threatening Ischemia. K. Kasiralan, University ofNew Mexico School ofMedicine, Albuquerque, NM, USA· K. Ouriel PURPOSE: The aim of the study was to evaluate percutaneous mechanical thrombectomy (PMT) in comparison to open surgical revascularization (OSR) for the treatment of acute limb ischemia. MATERIALS AND METHODS: Patients with acute limb threatening ischemia «14 days) were identified from a prospectively maintained computer registry. The endovascular group had 65 consecutive patients treated with the Angiojet catheter (Possis Medical, Minneapolis, MN) as a stand-alone (n=21) or with adjunctive phannacological thrombolysis (n=44). This group was compared to 79 consecutive patients having undergone open surgical revascularization. The major clinical end points evaluated include death, major amputation, major morbidity, primary patency and 12-month amputation free survival. RESULTS: There was a greater incidence of hypertension (P
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Abstract No. 224
FEATURED ABSTRACT
Commentator: Charles E. Ra) •.Jr.
Restoring Flow to Occluded Central Venous Catheters with Use of Alteplase: Safety and Efficacy in 1064 Patients. c.p Semba. BioTherapeutic Unit, Genentech, Inc., San Francisco, CA, USA· S.R. Deitcher • X Ii· L. Resnansky • PA. Hill· E.R. McCluskey
PURPOSE: Thrombosis of central venous access devices (CVADs) is a relatively frequent complication. Alteplase (tPA) has been used to salvage dysfunctional devices. The purpose of this study was to analyze the safety and efficacy following administration ofup to two 2 mg doses ofalteplase in restoring function to thrombosed CVADs. MATERIALS AND METHODS: A combined analysis was perfonned on two pivotal prospective Phase III clinical trials involving 79 centers from November 1999 through December 2000. Patients ~ 2 yrs ofage (and> 10 kg) with dysfunctional non-dialysis CVADs were eligible including PlCCs, apheresis catheters and ports. Alteplase (2 mg/2 mL) was instilled in the lumen of the cvAn and allowed to dwell. For patients with body weight 10 to < 30 kg, 110% of the internal lumen volume ofalteplase (2 mg/2rnL) was administer~d. Ifthe device was still occluded after up to 120 ro, a second alteplase dose was given and allowed to dwell for up to 120 m. Primary efficacy endpoint was restored function after up to 2 doses. Primary safety endpoint was ICH within 5 days. RESULTS: A total of 1070 patients (M 467: F 603; mean age 50.7 yrs, range, 2 - 91:) were eligible and 1064 (99.4%) were treated. Six (0.6%) pts had spontaneous function w/o treatment. Following alteplase, function was restored in 798 (75.0%) after one dose and 905 (85.4%) after up to 2 doses. Efficacy rates were similar among all catheter types (single, double, triple lumen catheters, ports). Serious adverse events reported within 30-days of treatment: ICH (0.0%), embolic events (0.0%), GI bleeding (0.3%), thrombosis (0.3%), and sepsis (0.4%). There were no gender-related differences observed in the rates of adverse events and were similar across age subgroups. CONCLUSION: AJteplase (2 mg/ 2mL) is safe and effective in restoring flow to occluded central venous access devices.
Scientific Session 29 Access Site Management/Closure Devices Thursday, April 11 ,2002 3:00 PM - 4:30 PM Moderator(s): Kenneth D. Murphy, MD
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Abstract No. 225
A Novel Access Method for Endovascular Procedures in the Swine Model. Y. Dong, The Cleveland Clinic Foundation, Solon, OH, USA • M Sands· P Rasmussen· J. Perl II PURPOSE: The saphenous artery arises from distal femoral artery and I ies just under the skin at the internal-middle of the thigh. This study evaluates the use of the saphenous artery as an al ternative access for endovascular procedures in the swine model. MATERIALS AND METHODS: Fourteen adult pigs (25-35kg) were used in this study, three pigs from an acute study and eleven from chronic studies. A 1-2 em incision was made and a saphenous artery cutdown was perfonned in 24 sides. Micropuncture sets (Boston Scientific) or 18 G puncture needles were used to access the artery. Different sizes of introducers (4-7 F) were used to establish endovascular access. Angiographic catheters were then used to confLTITI ifthe access was usable. Four saphenous arteries were explanted in the pigs from a chronic study one month after the surgical procedure.
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